Stable surface expression of MHC class I molecules is highly dependent upon full assembly of heavy chain with beta-2 microglobulin and peptide ligand. Furthermore, optimal assembly of class I has recently been shown to be dependent upon its interaction with an elaborate cascade of ER chaperone proteins, termed the peptide loading complex. After peptide binding, class I molecules are released from the loading complex and transit to the cell surface for detection by CD8+ cytolytic T cells. A remarkable recent finding is that viruses have developed elegant and diverse mechanisms to prevent class I expression. The experiments in this application will define the mechanism of class I down regulation used by homologous proteins expressed by mouse gamma-herpesvirus-68 and human Kaposi?s sarcoma-associated herpesvirus. Importantly, we have preliminary data showing that viral protein can be detected in association with class I prior to high affinity peptide binding. Thus we have the unique opportunity to determine whether viruses exploit known ER molecular chaperones in their down regulation of class I. Furthermore, definition of this pathway will provide key insights into how viral proteins uniquely identify class I assembly intermediates, and target them for degradation.